Abstract
There is a need for continued drug development for nonalcoholic steatohepatitis (NASH). Bergamot is a plant whose fruit juice is enriched with flavonoids and phenolic compounds which improves dyslipidemia and markers of systemic inflammation in patients with Metabolic Syndrome. The aim of this study was to perform a preclinical “proof of concept” study of Bergamot polyphenolic formulation (BPF99) for the treatment of NASH. A disease reversal study was performed in the diet-induced animal model of NAFLD (DIAMOND). Groups of 8 weeks old mice were randomly assigned to receive chow diet, high fat diet with sugar in drinking water (Western diet- WD). Mice on WD were further randomized to continue on WD gavaged with vehicle or continue on WD with additional gavage of BPF99 (50 mg/kg) after 16 weeks of diet. Mice were euthanized after 11 additional weeks. The primary endpoint was resolution of NASH. Secondary endpoints included changes in individual histological features, body weight, liver enzymes, dyslipidemia, markers of oxidative stress and molecular markers of disease activity and fibrosis. The results showed that BPF99 reduced ALT (mean 71.6 vs 44.6 IU/l, p < 0.01), triglycerides (38.8 vs 28.1 mg/dl, p < 0.05), LDL-C (39.2 vs 23.7 mg/dl, p < 0.001). It significantly improved NASH resolution (p < 0.001) and the SAF scores (p < 0.05) while the NAS improvement approached significance. BPF99 reduced markers of oxidative stress, along with reduced JNK and p38 MAP kinase activity. BPF99 did not reduce the number of mice with fibrosis but improved collagen proportional area (p < 0.04) and procollagen I and III expression. Collectively our results showed that BPF99 resolves NASH and ameliorates key histological and pathophysiological features of NASH along with improvement in ALT and dyslipidemia in the DIAMOND mice.
Highlights
Www.nature.com/scientificreports more likely to progress to cirrhosis[3,4]
As drug development efforts are currently focused on nonalcoholic steatohepatitis (NASH) and stage 2–3 fibrosis or cirrhosis[4], the treatment of the greatest burden of disease www.nature.com/scientificreports which characterizes either NAFL or NASH early remains an important unmet medical need because the patients still have excess cancer- and cardiometabolic risk[42]
We provide evidence of the potential benefits of BPF99 in a preclinical model of NASH
Summary
Www.nature.com/scientificreports more likely to progress to cirrhosis[3,4]. Excess liver-related mortality from NASH is mainly due to progression to cirrhosis and development of hepatocellular cancer. The cellular stress produced either directly by lipotoxicity or the cellular response to metabolic overload drives cell-death and inflammatory signaling via activation of the innate immune system[7]. In this scenario, some pathways including oxidative stress and the unfolded protein response[8,9] contribute to the development of chronic inflammation, inducing a fibrogenic response and progressive fibrosis leading to cirrhosis. The Citrus extract, rich in healthful phytochemical compounds, was able to protect human microvascular endothelial cells from LPS-induced activation and dysfunction, reducing the endoplasmic reticulum stress[23]
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